Our long-term goal is to understand how developing immune responses are regulated by effector cells of innate immunity. NK cells play a primary role in this regulation, and our preliminary data suggest that their physiological role(s) depend on their developmental stage, with immature and mature NK cells likely primarily involved, respectively, in maintaining non-adaptive immunity, and in regulating the development of adaptive responses. We have defined that immature CD161+CD56-NK cells have highest proliferative potential in response to interleukin (IL)-4, can not mediate granule exocytosis-dependent cytotoxicity and produce cytokines that primarily affect myeloid and B cells [i.e. tumor necrosis factor (TNF)-alpha, Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF), and the type 2 cytokines interleukin (IL)-5 and IL-13]. These cells, present in the periphery, develop, transiting through an IL-13+ Interferon (IFN)-gamma+ stage, into terminally differentiated, phenotypically mature CD56+ cells that exert granule exocytosis- and Fas-ligand (L)-mediated cytotoxicity, have decreased ability to produce TNF-alpha and GM-CSF, are IL-13-, and produce exclusively IFN-gamma, and finally IL-10 as they undergo apoptotic cell death. This poses the basis for our working hypothesis that qualitative modulation of peripheral NK cell functions is achieved primarily via modulation of the terminal linear development of the immature peripheral NK cells by any factor (cytokine or cellular interaction) that retards it by inducing their proliferation-dependent accumulation, or accelerates it by inducing changes that allow the cells to respond to IL-12 and other yet-to-be defined differentiation-inducing stimuli. Our additional observation that this developmental process is shared with T cells leads us to predict that the same cytokines may regulate it both T and NK cells, and that one or more receptor(s) involved in target cell recognition in NK cells may share with the TCR functions other than ligand recognition. This working hypothesis will be tested in 3 Specific Aims: 1) To determine the role of IFN and other selected cytokines in terminal NK cell development; 2) To define the regulation and function (other than cytotoxicity) of "activating" receptors on NK cells; 3) To analyze the possibility that NK cells derive from a common (type 2 cytokine +) peripheral T/NK cell progenitor cell. The results of these studies are expected to pose the bases for rational manipulation of the innate system for cytokine-based and/or immunotherapeutic and preventive interventions (e.g. vaccinations to pathogens like viruses and tumors). Also, defining how immature peripheral cells, present in any individual, can be maintained and/or induced to differentiate to functionally mature lymphocytes is relevant to the possibility of genetic manipulation of innate immunity and its reconstitution in numerous clinical settings.